Opiates, the alkaloids derived from opium, have long been used to alleviate pain and suffering in humans. Unfortunately, opiates have also been used as illicit narcotics. The unique ability of these compounds to elicit an analgesia accompanied by euphoria has captured the interest of mankind for more than five thousand years, e.g., see P. T. White, et al., National Geographic, 1985, vol. 167, p. 142.
Opium (the dried latex of unripe poppy plant capsules) contains over 40 alkaloids. The chief alkaloid constituent of opium is morphine, which is present in varying amounts of 5 to 24% depending on the opium source. Codeine is the opiate of most interest to the pharmaceutical industry. However, codeine is available from natural sources such as opium and poppy straw only in limited quantities, e.g., 2–4%. Since the demand for codeine far exceeds the available natural supply, there is a continuous search for a synthetic method that is capable of producing codeine of high purity in large amount. The pharmaceutical industry is particularly interested in producing codeine in the most cost effective and environmentally friendly manner possible.
It is known that morphine may be methylated at the phenolic hydroxy end (i.e., position 3) to obtain codeine. However, an undesired second methylation at the free hydroxyl end (i.e., position 6) also occurs, e.g., see S. Pfeifer, Pharmazie, 1963, vol. 18, p. 409 and E. Brochmann-Hannsen et al., J. Pharm. Sci., 1967, vol. 56, p. 1207. Another competing reaction at the nitrogen end (i.e., position 17) leads to yet another undesirable product, e.g., see W. Debska et al., Chem. Anal. (Warsaw), 1979, vol. 24, p. 407; C. Mannich, Arch. Pharm., 1916, vol. 254, p. 349; and B. Proksa et al., Chem. Zvesti., 1983, vol. 37, no. 6, pp. 837–842.
A variety of methylating agents has been reported in the scientific literature as being capable of converting morphine to codeine, see W. Heumann, Bull. Narcotics, 1958, vol. 3, p. 15. The earliest attempt to convert morphine into codeine dates back to 1881 and involved the use of methyl iodide, a commonly used methylating agent (see M. Grimaux, C. R. Acad. Sci., 1881, vol. 92, p. 1140). Alkylating agents such as methyl chloride (see M. A. Phillips, Chemist Druggist, 1965, vol. 183, pp. 661 and 4454), dimethyl sulfate (see, M. A Phillips, Ibid. and German Patent 418,391), diazomethane (see H. von Pechmann, Ber., 1894, vol. 27, p. 1888; Ibid. 1895, vol. 28, p. 1624 and other reagents (see German Patent 39,887; and L. Small et al., Chemistry of the Opium Alkaloids, 1932, US Gov. Printing Office, p. 175) have also been employed in the past. However, virtually all of these prior art methods are accompanied by an uncontrollable decomposition reaction, thereby rendering them of limited value from a commercial standpoint.
One of the biggest disadvantages of methylation reactions is that the nitrogen of the morphine readily reacts with the methylating agent resulting in quaternary ammonium species. These ammonium compounds undergo further degradation compromising both yield and purity. With the introduction of quaternary ammonium reagents containing methyl groups as methylating agents these problems have been greatly reduced. Phenyltrimethylammonium chloride or a modification of it has become the reagent of choice for the manufacture of codeine from morphine since its launch in 1909, see German Patent 247180. Rodionov (Bull. Soc. Chim. (France), 1926, vol. 4, no. 39, p. 305) was the first to use the free quaternary ammonium base in lieu of the corresponding chloride. Use of quaternary ammonium bases in the form of alkoxides was among the improvements made to optimize the methylation process, see C. K. Ingold et al., J. Chem. Soc. (London), 1933, vo. 1, p. 69; and K. Ikonovski, Acta. Pharm. Jugoslav., 1973, vol. 23, pp. 169–171; Ibid., 1982, vol. 32, pp. 241–246; and U.S. Pat. No. 6,579,985. More recently, Ayyangar et al. (U.S. Pat. No. 4,764,615) have disclosed a method to prepare codeine using phenyltrimethylammonium chloride in the presence of an alkali metal carbonate. O-Methylation of phenols with phenyltrimethylammonium chloride has also been reported (see Carlsen et al. Acta Chemica Scandinavica, 1997, 51, pp. 343–344). A solid-phase synthesis using a polymer-bound methylating agent is a new variation in methylating morphine to codeine (see U.S. Pat. No. 5,981,750).
All of the known synthetic routes employ rigorous conditions (very high temperatures and/or high pressures, strong alkaline media, or hazardous reagents/byproducts) and are regularly plagued by problems such as competing secondary reactions, incomplete alkylation, excessive alkylation and/or low yields. Currently, nearly all of the industrial conversions of morphine to codeine are carried out using quaternary ammonium salts. According to reported procedures employing phenyltrimethylammonium chloride it is imperative that exact stoichiometric quantities of morphine and the methylating agent be used to minimize secondary products. Under industrial conditions, an adverse dimethylated product (6-methylcodeine) is invariably produced. In large-scale productions of codeine, it is customary to use morphine in slight stoichiometric excess over the methylating agent to minimize the formation of the over-methylated product. In these cases, however, the unreacted morphine must be removed at the end of the reaction, resulting in additional capital and production costs.